N-substituted desoxynorcodeine compounds



United States Patent N SUBSTITUTED DESDXYNORCODEINE COB POUNDS Robert L. Clark, Woodbridge, and Karl Pfister 111, Westfield, N. 3., assignors to Merck 8; (30., End, Railway, N. 1., a corporation of New Jersey No Drawing. Application November 22, 1952, Serial N0. 322,141

12 Claims. (Cl. 260-235) This invention is concerned generally with novel deriva tives of morphine and with processes for preparing these morphine derivatives. More particularly, it relates to novel N-substituted desoxynorcodeine compounds having attached to the nitrogen atom the terminal carbon of a straight aliphatic chain consisting of three carbon atoms, to acid salts thereof, and to novel processes for preparing these compounds starting with desoxynorcodeine or with the corresponding N-substituted desoxynorcodeine compound. These N-substituted desoxynorcodeine compounds, and salts thereof, are active as morphine antagonists.

The N-substituted desoxynorcodeine compounds, and acid salts thereof, subject of the present invention, may be chemically represented by the following structural formulae:

OCH; OCH;

NY N-BA wherein Y is an aliphatic radical containing a straight chain consisting of three carbon atoms a terminal carbon of which is attached to the nitrogen atom, and HA is an acid. 1

The chemical relationship of these N-substituted desoxynorcodeine compounds to morphine is clear from a comparison of the foregoing formulae with the formula for morphine which is as follows:

N-CH:

Whereas the alkaloid morphine is a potent analgesic, we have found that N-substituted desoxynorcodeine compounds having attached to the nitrogen atom the terminal carbon of a straight aliphatic chain consisting of three carbon atoms, in particular N-n-propyldesoxynorcodeine, N-isobutyldesoxynorcodeine, N-allyldesoxynorcodeine, N- methallyldesoxynorcodeine, and acid salts thereof do not posses any significant analgesic action but, instead, are strong -morphine antagonists'and prevent or abolish the analgesic: action of morphine when utilized in conjunction with that drug. This antagonistic action possessed by the subject compounds is particularly surprising in 2,741,610 Patented Apr. 10, 1956 OCH: OCH:

Compound 1 Compound 2 Compound 3 wherein Y is an aliphatic radical containing a straight chain consisting of three carbon atoms a terminal carbon of which is attached to the nitrogen atom, X is a halo radical, and HA is an acid.

The reactions indicated hereinabove are carried out as follows: Desoxynorcodeine (Compound 1) is reacted with an aliphatic halide of the formula Y-X wherein X and Y have the significance defined hereinabove, thereby forming the corresponding N-substituted desoxynorcodeine compound (Compound 2); the latter compound is reacted with an acid to produce the corresponding salt of said N-substituted desoxynorcodeine compound (Compound 3).

The desoxynorcodeine, which is used as a starting material in our novel process, is a new compound which can be prepared by reacting the desoxycodeine with cyanogen bromide in a solvent. Suitable media for this reaction are nonpolar solvents for desoxycodeine such as benzene, toluene, chloroform and carbon tetrachloride. Chloroform is the preferred solvent for this reaction. The reaction is preferably carried out at reflux temperatures so that the methyl bromide is expelled as formed. The reaction time does not appear to be critical; however, a reflux period of from one to five hours appears to be suflicient. ether to precipitate desoxycodeine methyl bromide formed during the reaction; the latter is removed by filtration and the filtrate concentrated under reduced pressure to a small volume from which N-cyanodesoxynorcodeine may be recovered.

The step of converting N-cyanodesoxynorcodeine to desoxynorcodeine involves both hydrolysis of the nitrile and decarboxylation of the carboxylic acid thus formed. This may be accomplished by heating N-cyanodesoxynorcodeine with an aqueous solution of a non-oxidizing mineral acid. The concentration of the mineral acid is not critical and good results have been obtained by employing one-half normal hydrochloric acid. It has been found advantageous to add a small amount of a lower aliphatic 'carboxylic acid such as acetic acid to the re action mixture. The mixture is then heated to a temperature of about 70-l00 C. until the evolution of carbon dioxide has ceased. The reaction mixture is then cooled, neutralized and desoxynorcodeine extracted into a suitable organic solvent such as diethylether; the solvent is evaporated from this extract, preferably under reduced pressure to give the desired desoxynorcodeine.

The aliphatic halides which react with desoxynorcodeine to form our novel N-substituted desoxynorcodeine com- The cooled reaction mixture is diluted with desoxynorcodeine acetate, N-n-propyldesoxynorcodeine tartrate, N-isobutyldesoxynorcodeine hydrochloride, N- isobutyldesoxynorcodeine hydrobromide, N-isobutyldesoxynorcodeine sulfate, N-isobutyldesoxynorcodeine acetate, N-isobutyldesoxynorcodeine tartrate, N-allyldesoxynorcodeine hydrochloride, N-allyldesoxynorcodeine hydrobromide, N-allyldesoxynorcodeine sulfate, N-allyldesoxynorcodeine acetate, N-allyldesoxynorcodeine tartrate, N-methallyldesoxynorcodeine hydrochloride, N- methallyldesoxynorcodeine hydrobromide, N-methallyldesoxynorcodeine sulfate, N-methallyldesoxynorcodeine acetate, N-methallyldesoxynorcodeine tartrate, and the like. The salt thus formed is recovered from the alcoholic slurry by filtration or centrifugation.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 A mixture of 4 g. of desoxynorcodeine, 1.78 g. of sodium bicarbonate, 2.52 g. of n-propyl iodide and 50 ml. of absolute ethanol was heated under reflux with stirring for a period of about twenty-four hours. At the end of this period some insoluble material was present and was removed by filtration. The filtered solution was evaporated to dryness under reduced pressure; the residual material was slurried with several portions of diethyl ether, and the ethereal extract was filtered. The filtered ethereal solution was concentrated in vacuo to give N-n-propyldesoxynorcodeine which was obtained in the form of an oil which crystallized upon cooling.

The N-n-propyldesoxynorcodeine was reacted with ethanolic hydrogen bromide, and the crystalline product which separated was recovered by filtration and purified by recrystallization from ethanol-ether to give substantially pure N-n-propyldesoxynorcodeine hydrobromide; M. P. 28l283 C. [a] =34 (c, 0.8 in ethanol).

Analysis.-Calculated for CzuHzsNoz-HBrz C, 61.23; H, 6.68. Found: C, 60.93; H, 6.88.

The descoxynorcodeine utilized as starting material in the foregoing process was prepared in accordance with the following two-step procedure: (1) A solution of 7.8 g. of cyanogen bromide in 25 ml. of dry chloroform was stirred and heated under reflux while adding thereto, dropwise over a period of one hour, a solution of 19.0 g. of desoxycodeine in 45 ml. of dry chloroform. The resulting solution was heated under reflux for an additional period of five hours. The reaction mixture was cooled and diluted with 400 ml. of ether. The ethereal solution was separated from the gummy material which precipitated by filtration and the filtered ethereal solution was evaporated to small volume under reduced pressure. The concentrated solution was cooled and the crystalline material which separated was recrystallized from ethyl acetate to give substantially pure N-cyanodesoxynorcodeine; M. P. 149-150" C.; [u] =-l30 (c, 0.75 in absolute ethanol).

Analysis.Calculated for CtsHtaNzOa: C, 73.45; H. 6.16. Found: C, 73.60; H, 6.20.

(2) A mixture of 33 g. of N-cyanodesoxynorcodeine, 128 ml. of glacial acetic acid, 45 ml. of concentrated aqueous hydrochloric acid and 900 ml. of distilled water was heated at a temperature of about 90 C. for a period of about ninety hours. The resulting reaction mixture was decolorized by filtration through a mat of activated charcoal. The substantially decolorized, light-yellow filtrate was cooled to about room temperature and an aqueous solution of ammonium hydroxide was added thereto portionwise, whereupon an oil separated. The portionwise addition of the aqueous ammonium hydroxide was continued until no further oil separated. The resulting mixture was then extracted with three portions of ether, the combined ethereal extracts were dried over magnesium sulfate and the ether was evaporated from the dried ethereal solution under reduced pressure. The residual crystalline material was recrystallized from ether to give substantially pure desoxynorcodeine; M. P. -86 C.; [u] =-59 (c, 1.2 in obsolute ethanol).

Analysis.Calculated for C17H19NO20: C, 75.78; H, 7.11. Found: C, 74.67; H, 6.89.

Example 2 V A solution of 3.25 g. of N-allylnorcodeine in 3.2 ml. of dry pyridine was cooled to a temperature of about 10 C. and to the cold solution was added a solution of 2.2 g. of p-toluene sulfonylchloride in 2.2 ml. of dry pyridine. The resulting mixture was allowed to stand at a temperature of 0 C. for a period of four hours and the reaction mixture was then poured into ml. of cold water containing 1.5 g. of sodium bicarbonate. The gummy material which precipitated was recovered by decantation, washed with cold water and extracted with chloroform. The chloroform extract was washed with water, then with an aqueous solution of sodium bicarbonate, and again with water. The chloroform was evaporated under reduced pressure from the washed chloroform extract, and the residual gummy material was dissolved in ether. To this ether solution was added an excess of ethanolic hydrogen bromide, and the crystalline material which precipitated was recovered by filtration and recrystallized from methanol to give substantially pure 6-(p-toluenesulfonyl)-N-allylnorcodeine hydrochloride; M. P. -l46 C. This material was dissolved in water, dilute aqueous sodium hydroxide was added to the solution, and the resulting aqueous alkaline mixture was extracted with ether. The ethereal extract was washed with water, dried and the'ether evaporated to give crystalline 6-(p-toluenesulfonyl)-N-allylnorcodeine; M. P. 110-111 C.

A solution of 2 g. of 6-(p-ptoluenesulfonyD-N-allylnorcodeine in 20 ml. of purified tetrahydrofuran was slowly added to a solution of 0.6 g. of lithium aluminum hydride in 30 ml. of purified tetrahydrofuran. After the initial mildly exothermic reaction had subsided, the mixture was heated under reflux for a period of four hours. Fifty milliliters of ether was added to the reaction mixture followed by the dropwise addition of water to decompose unreacted lithium aluminum hydride. The crystalline material which precipitated was recovered by filtration and dissolved in hot ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulfate, and the dry ethereal solution was evaporated to dryness. The residual material was recrystallized from ether to give substantially pure N-allyldesoxynorcodeine; having a melting point of 75-77 C., [a] =98 (c, 1.0 absolute ethanol).

Analysis-Calculated for C20H23N022 C, 77.63; H, 7.49. Found: C, 77.93; H, 7.36.

The N-allylnorcodeine utilized as starting material in the foregoing process can be prepared in accordance with the following two-step procedure: (1) thirty-five grams of normorphine and 7.95 g. of allyl bromide is dissolved in 350 cc. of chloroform and the solution is heated in a sealed tube at a temperature of 110 C. for a period of three and one-half hours. The reaction mixture is filtered, and the residual solid material extracted with chloroform. The chloroform extract is evaporated to dryness in vacuo, and the residual material is triturated with 75 cc. of ether. The resulting mixture is cooled to approximately 0 C. and maintained at that temperature for a period of about two hours. The precipitated material is recovered from the resulting slurry by filtration, and is extracted for fifteen hours with anhydrous ether utilizing a Soxhlet extractor. The ether extract is evaporated in the absence of air to incipient crystallization, cooled to 0 C. and maintained at that temperature for a period of about fifteen hours. The crystalline material which separates is recovered by filtration, washed with ether and dried in vacuo to give substantially pure N-allylnormorphine; M. P. 208-209 C.

anytime;

2) Oneiequivalentrrweightofnphenyltrhnethylammm nium tchlorideris; added-.10 an ethanol :solutionccontaining: appiioximatelyp one-equivalent weightzofzsodiumzethoxidea The resulting mixmredsgfilteredlltherebyremoving-theprecipitated sodiumchloride; and tozthefilteredethauolic solution containing approximately onetequivalentoflphenv yltrimethylammonium hydroxide is, added one equivalent Weight of N-allylnormorp'hine. The resulting mixture is heated and theethanol distilled-therefrom:untilthe. temperature-of thedistillandiiaapgroximately 120? C, The reaction. mixture is then cooled and. an excess ofacetic acid (approximately.- 1.2: equivalents) is added to the cooled mixture; The resulting mixture is subjected to steam distillation therehy isteam-l distilling the by -p roductz dimethy-l aniline; To heaqileousrdistillandisadded .sufii:- cientaqueous:sodium, hydroxide solution to render the mixture slightly alkaline,v and-this aqueous, alkaline mightureis extractedi with chloroform, The: chloroform is evaporated from the resulting tchloroiormextract, andithe:

residual crystalline-material is- -Washedwithether and-V consistsof;N mpronylshalidest Ndsobntykhalidesrkailyl; diN methallyllhalides, to; form; the: corr spond.

7.. IhQZPIDCESS/ihfil comprises reaeting -desoxynorcode ine1with an in-propyl ihalideto rformvN-ngpropyldesoxynorr codeine.- 7

8 The process: thatcomprises, reacting-desoxynorcode ine withsanxallylhalideitoform N-allyldesoxynoreodeine; V 9; Thez'processgthat comprises reactinganN-substituted: norcodeine: compound-v having attached; to" the: nitrogen-.

atoms a; radical selected. from theigroup consisting, of; Nenwpropyl, N-isohutyl, N-allyl andN-methallyl-radicals:

with a sulfonyl halide-j to form N-substituted:6-(organic:

sulfonyD-norcodeine, and reacting: the; latter compound with. lithium [aluminum hydride eto 'formzthescorresponding Nasubstituteddesoxynorcodeine: V

1.0. The process-thatcomprises reactingrNen-propylnan codeine with p-toluene sulfonyl halide to formad-(P-tolu enesulfonyl) -N-n-propylnoroodeine;and reacting the latter compound with-lithium aluminumhydride to form the compound N-n-propyldesoxynorcodeine,

'11. The, process that comprises reacting N-allylnorcm deine. with a p toluene'sulfonyl'halide to' form 6-(p=toluenesulfonyl)-N allylnorcodeine and reacting the latter compound with lithium aluminum hydride to form thecompound'N-allylnorcodeine.

l2; Nr-n-propyldesoxynorcodeine sulfate.

RefgrencesC-ited-in'the; file of-this patent SIATES PATENT Small V..- .Oet."31, 1939;

' OTHER REFERENCES- .w Manskeet-al: TheAlkaloids, Academic'Press (1952),; M n

Small,,J..-: Org. Chem., vol. 3, p 214 (1938).

the t 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF AN N-SUBSTITUTED DESOXYNORCODEINE COMPOUND HAVING ATTACHED TO THE NITROGEN ATOM A RADICAL SELECTED FROM THE GROUP CONSISTING OF N-N-PROPYL, N-ISOBUTYL, N-ALLYL AND N-METHALLYL RADICALS, AND ACID ADDITION SALTS THEREOF. 